Over the past 10 years the agouti/melanocortin system has become recognized as a major regulator of bodyweight homeostasis. For example, a greater number of mutations in the agouti/melanocortin signaling pathway are linked to obesity in humans than any other pathway. The basic paradigm is that melanocortins bind to a family of receptors and reduce bodyweight. Agouti and agouti related protein (AGRP) are endogenous antagonists of melanocortin receptor binding. Moreover, the chronic antagonism of melanocortin receptors by agouti/AGRP leads to obesity. Our preliminary data clearly demonstrate that humans express and regulate agouti in adipose tissue. Therefore, it is important to determine the impact of agouti/melanocortin signaling in fat on obesity and diabetes. The focus of ongoing studies in my laboratory is to understand the function of agouti/melanocortin signaling in adipose tissue and evaluate its contribution to obesity and diabetes. Data collected from transgenic mice that overexpress agouti in adipose tissue and studies in cultured adipocytes have led us to propose that agouti/melanocortins are part of a communication circuit between the brain and adipose tissue which conveys centrally-mediated signals (ACTH and alpha-MSH) and modulates adipocytes responsiveness to these signals (agouti). The overall hypothesis is that Agouti/melanocortins regulate adipogenesis and adipocyte metabolism at several levels. First, we hypothesize that agouti increases the proliferation of preadipocytes. Our second hypothesis is that agouti promotes the differentiation of preadipocytes into mature adipocytes. Third, we predict that agouti alters cAMP-dependent signaling pathways in the mature adipocyte such that it is more resistant to lipolysis and more efficient at storing triglycerides. The focus of this proposal is to understand both the mechanisms of agouti/melanocortin action on preadipocytes and adipocytes and the basis for how these effects on adipocyte function contribute to obesity. The preliminary data in this proposal demonstrate that the agouti/melanocortin system is potentially one of the major regulators of adipocyte function, just as it is a major regulator of bodyweight homeostasis, This makes a strong case for studying agouti/melanocortin signaling in adipose tissue and its relevance in understanding the underlying mechanisms of obesity.